Project Summary Overall response to the epidermal growth factor receptor (EGFR) inhibitor cetuximab is poor and resistance, both intrinsic and acquired, is a critical issue. Therefore it is imperative to elucidate the mechanisms of poor response to cetuximab and develop strategies to enhance tumor response to cetuximab and improve patient outcomes. My overall research interests center around inflammation and immune response as key mechanisms of tumor progression in HNSCC patients and poor tumor response to cetuximab. My dissertation research focuses on the IL-1 pathway as an important player in tumor response to cetuximab in HNSCC patients and the overall hypothesis of my dissertation research is that IL-1 blockade will improve the anti- tumor efficacy of cetuximab in HNSCC. Findings from my dissertation research project thus far strongly support this hypothesis indicating that IL-1 blockade using a neutralizing IL-1 alpha (IL-1?) antibody increased HNSCC tumor response to cetuximab in xenograft mouse models and that IL-1? may be an important biomarker to predict tumor response to cetuximab for HNSCC patients. For the remainder of my dissertation research project, I will continue to test my hypothesis using the FDA approved IL-1 receptor antagonist (IL- 1RA) anakinra in combination with cetuximab in HNSCC mouse models, and assess potential mechanisms of tumor response to combination drug therapy. Finally, during my postdoctoral period I am interested in combining anti-IL-1 therapy with anti-CTLA4/PD1 therapy for HNSCC since the current trend in cancer therapy including HNSCC is to activate the immune system using anti-CTLA4/PD1 therapies. Overall, I believe that this F99/K00 award will assist me in establishing my research career focused on inflammation and immune response as important players in tumor response to drug therapy and pave the way for me to become a successful independent investigator.